Krüppel-like factor 3 inhibition by mutated lncRNA
| Autor: | Mi, Yang, Qi, Guo, Hui, Peng, Yu-Zhong, Xiao, Ye, Xiao, Yan, Huang, Chang-Jun, Li, Tian, Su, Yun-Lin, Zhang, Min-Xiang, Lei, Hui-Ling, Chen, Tie-Jian, Jiang, Xiang-Hang, Luo |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male China Heterozygote Sialoglycoproteins Kruppel-Like Transcription Factors Neovascularization Physiologic Article Cohort Studies Mice Young Adult Bone Density Osteogenesis Spirostans Animals Humans Research Articles Aged Endothelial Progenitor Cells Aged 80 and over Mice Knockout Middle Aged Saponins Hyperostosis Cortical Congenital Mice Inbred C57BL Platelet Endothelial Cell Adhesion Molecule-1 Osteopetrosis Mutation Female RNA Long Noncoding |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 |
| Popis: | The authors report a mutation in the long noncoding RNA Reg1cp that induces osteogenesis via vascular induction in humans. This mutation affects angiogenesis by blocking Klf3’s repressing activity. The Klf3 antagonist Ophiopogonin D could promote CD31hiEmcnhi vessel formation and osteogenesis in osteoporosis mice. High bone mass (HBM) is usually caused by gene mutations, and its mechanism remains unclear. In the present study, we identified a novel mutation in the long noncoding RNA Reg1cp that is associated with HBM. Subsequent analysis in 1,465 Chinese subjects revealed that heterozygous Reg1cp individuals had higher bone density compared with subjects with WT Reg1cp. Mutant Reg1cp increased the formation of the CD31hiEmcnhi endothelium in the bone marrow, which stimulated angiogenesis during osteogenesis. Mechanistically, mutant Reg1cp directly binds to Krüppel-like factor 3 (KLF3) to inhibit its activity. Mice depleted of Klf3 in endothelial cells showed a high abundance of CD31hiEmcnhi vessels and increased bone mass. Notably, we identified a natural compound, Ophiopogonin D, which functions as a KLF3 inhibitor. Administration of Ophiopogonin D increased the abundance of CD31hiEmcnhi vessels and bone formation. Our findings revealed a specific mutation in lncRNA Reg1cp that is involved in the pathogenesis of HBM and provides a new target to treat osteoporosis. |
| Databáze: | OpenAIRE |
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